Cardiac Amyloidosis

Corresponding Author

The proteins have an unstable structure that causes them to misfold, aggregate, and deposit as amyloid fibrils.The origin of the misfolded protein in cardiac amyloidosis is typically either monoclonal immunoglobulin light chains (AL) from an abnormal clonal proliferation of plasma cells, or transthyretin amyloidosis (ATTR), a liver-synthesized protein that is normally involved in the transportation of the hormone thyroxine and retinol-binding protein.
ATTR amyloidosis is more common than AL amyloidosis and can be inherited as an autosomal dominant trait caused by pathogenic variants in the transthyretin gene TTR (ATTRv) or by the deposition of wild-type transthyretin protein (ATTRwt).[3] Several critical advances in the diagnostic approach, coupled with approval of effective therapies, have elevated cardiac amyloidosis to a position of diagnostic prominence. 4First, imaging techniques and monoclonal protein testing now allow for accurate noninvasive diagnosis of ATTR cardiac amyloidosis 5 without the need for confirmatory endomyocardial biopsies.Second, observational studies indicate that ATTR cardiac amyloidosis may be under-recognized in a significant proportion of patients with heart failure. 6,7Third, prompt implementation of therapeutic interventions, namely tafamidis, can improve survival, physical function, and/or quality of life. 8,9th these advances over the past decade, there has been a substantial increase in diagnosis of ATTR cardiac amyloidosis, with more patients diagnosed at an earlier stage of the disease with substantially lower mortality over time. 10The impact of increased awareness on prompt recognition, appropriate diagnosis, and timely treatment also can be inferred from comparison of outcomes in the 2 landmark clinical trials in ATTR cardiac amyloidosis.The Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT) enrolled patients from December 2013 through August 2015. 9After 30 months, 42.9% of patients receiving placebo had died, compared with 29.5% of patients receiving tafamidis.In contrast, the Efficacy and Safety of AG10 in Subjects with Transthyretin Amyloid Cardiomyopathy (ATTRibute-CM) trial enrolled patients from April 2019 through October 2020 and, after 30 months, 24.2% of patients in the placebo group had died, compared with 17.8% of patients receiving acoramidis. 8The fact that patients in the placebo group in ATTRibute-CM had 30-month mortality that was lower than that of patients in the treatment group in the ATTR-ACT trial suggests improvements in other aspects of amyloid care over the ensuing almost 5 years between trial enrollments, including earlier diagnosis.
Currently, the only evidence-based, guidelinerecommended, and FDA-approved therapy for ATTR cardiac amyloidosis is tafamidis, 9 a TTR stabilizer, with promising clinical trial findings for acoramidis another stabilizer. 8

FUNDING SUPPORT AND AUTHOR DISCLOSURES
The author has reported that they have no relationships relevant to the contents of this paper to disclose.
As this study by Mora-Ayestaran et al demonstrates, these factors should not be discounted, even if the patient does not fit the typical demographic of age and sex.
Because TTR stabilizers inhibit the dissociation of the stable TTR tetramers into monomers, an essential step in fibril formation and subsequent tissue deposition, these agents do not reverse disease; once initiated, they only slow progression.Thus, early recognition and diagnosis of ISSN 2772-963X https://doi.org/10.1016/j.jacadv.2024.101087From the Department of Cardiologist, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.The author attests they are in compliance with human studies committees and animal welfare regulations of the author's institution and Food and Drug Administration guidelines, including patient consent where appropriate.For more information, visit the Author Center. 3However, this means that patients under 70 years of age, as well as women, may experience delays in diagnosis.Given this, a better understanding of the age and sex differences in clinical manifestations may reduce demographic diagnostic bias and allow for increased awareness and earlier treatment in typically underrepresented groups.In the context, the study by Mora-Ayestaran et al 11 in this issue of JACC: Advances used THAOS (Trans-